The expression “treatment of alcoholism” comprises the reduction of the desire for and habit of consuming alcoholic drinks, the treatment of alcohol dependence and the treatment of abstinence syndrome. Alcoholism may be viewed as a disease, a drug addiction, a learned response to crisis, a symptom of an underlying psychological or physical disorder, or a combination of these factors. Most approaches to the treatment of alcoholism require the alcoholic person to recognize his/her illness and to abstain from alcohol. Treatment programs then vary according to the accepted definition and theory of cause of alcoholism. Treatment types include combinations of: psychological rehabilitative treatments; organized self-help groups; aversion therapy based on behavior modification; injections of vitamins or hormones, and the use of abstinence-maintaining drugs. The present invention relates to the latter type of treatments.
One of the drug treatments of alcoholism, initiated in 1948 by Eric Jacobsen of Denmark, uses disulfiram (tetraethylthiuram disulfide), of formula Et2N—C(═S)—S—S—C(═S)—NEt2. The usual technique is to administer half a gram in tablet form daily for a few days; then, under carefully controlled conditions and with medical supervision, the patient is given a small drink of an alcoholic beverage. The presence of disulfiram in the drinker's body causes a reaction of hot flushing, nausea, vomiting, a sudden sharp drop of blood pressure, pounding of the heart, and even a feeling of impending death. These symptoms, usually known as “acetaldehyde syndrome” or “efecto adverso tipo-disulfiiram”, result from an accumulation of the highly toxic first product of alcohol metabolism, acetaldehyde. Normally, as alcohol is converted to acetaldehyde, the latter is rapidly converted, in turn, to other harmless metabolites; but in the presence of disulfiram—itself non-toxic, although not completely innocuous—the metabolism of acetaldehyde is blocked, with the resulting toxic symptoms. The patient is thus dramatically shown the danger of attempting to drink while under disulfiram medication. A smaller daily dose of disulfiram is then prescribed, and the dread of the consequences of drinking acts as a chemical fence to prevent the patient from drinking as long as he continues taking the drug.
Besides being quite unpleasant for patients, treatment of alcoholism with disulfiram involves a high risk, because subjects treated with disulfiram suffer from very serious symptoms deriving from the ingestion of even small doses of alcohol. Thus, following disulfiram treatment cases of respiratory depression, cardiovascular collapse, cardiac arrhythmia, myocardium infarct, and sudden or unexpected death have occurred.
Citrated calcium cyanamide (two parts of citric acid by weight to one part of CaNCN) is another drug used as anti-alcoholism agent, which has a disulfiram-like mechanism of action. It is preferred by some therapists because the reaction with alcohol is milder than in the case of disulfiram, though its protective potency is briefer. Other substances that can produce disagreeable reactions with alcohol include animal charcoal, the mushroom Coprinus atramentarius, numerous antidiabetic drugs, and the pine Lycopodium selago; however they have attracted very little clinical interest. Thus, in the last years, there have been an active research of other drugs to fight alcoholism without having the “disulfiram-like adverse effect”, i.e., without producing disagreeable reactions with alcohol.
Many anti-alcoholism agents have been proposed, among which there are the following: opioid antagonists, such as naltrexone, naloxone and nalmefene (cf. U.S. Pat. Nos. 4,882,335 and 5,086,058); acyl L-carnitine gamma-hydroxybutyrates (cf. EP 616,805-A1), gamma-hydroxybutyric acid salts (cf. U.S. Pat. No. 4,983,632) and gamma-hydroxybutyric acid amides (cf. WO 9806690-A1); 2-pyrimidinyl-1-piperazine derivatives such as ipsapirone (cf. U.S. Pat. No. 4,895,848); pyrrolidine derivatives (cf. U.S. Pat. No. 5,935,980); cholinesterase inhibitor, such as galanthamine (cf. U.S. Pat. No. 5,932,238); serotonin reuptake inhibitors, such as fluoxetine, and the combination of the later with opioid antagonists (cf. WO 9609047-A1).
Acamprosate calcium (cf. U.S. Pat. No. 4,355,043), of formula (CH3—CO—NH—CH2—CH2—CH2—SO3)2Ca , is one anti-alcoholism agent which is being used in practice. However, it has been mentioned that the use of this compound is far from being satisfactory, and that the evidence is not strong enough to support the introduction of this substance into routine clinical practice at present (cf. Moncrieff et al., “New drug treatments for alcohol problems: a critical appraisal”, Addiction 1997, vol. 92, pp. 939–47; discussion in pp. 949–64). Thus, apparently none of the proposed treatments of alcoholism has proved to be completely satisfactory in practice, and the pharmacological fight against alcoholism is far from being solved.
Endogenic polyamines putrescine, spermidine and spermine are compounds occurring in almost all tissues, essential for both normal and neoplastic tissue growth. They regulate DNA, RNA, and protein synthesis; stabilize ribosomes, membranes, and nucleic acids; and protect the cell against lipid peroxidation. They are metabolically related, putrescine being precursor of spermidine, and the latter precursor of spermine. These three polyamines, together with the closely related 1,3-propanediamine, are well known in chemistry.
For the treatment of alcohol and drug dependence, patent application WO 9948500 proposes the combination of an opioid antagonist (naltrexone, naloxone) with a N-Methyl-D-aspartic acid (NMDA) receptor complex modulator, particularly a spermidine site modulator such as acamprosate. However, in this document spermidine itself is neither mentioned nor suggested as an active agent for the treatment of alcoholism.
It is known that higher levels of the endogenic polyamines are found in cells that are dividing (e.g. in cancer cells) than in cells that are stable. Therefore, the concept of influencing the polyamine level in cells has been recognized and made use in chemotherapy, for example of cancerous diseases. As a consequence, these polyamines and several of their derivatives have been proposed as anti-neoplastic, anti-viral or anti-retroviral agents. Thus, for instance, patent U.S. Pat. No. 5,834,486 teaches the preparation of new substituted piperidinyl-2-alkyl linear polyamines and their use for reduction of intracellular levels of endogenic polyamines such as putrescine, spermidine and spermine. The new compounds are said to be useful for the therapeutic or prophylactic treatment of pathological conditions that are responsive to a reduction in the concentration of polyamines in cells, for example proliferative diseases, especially benign and malignant tumor diseases. Moreover, it is said that the new compounds can be used for treating protozoal infections, for example, trypanosomiasis and malaria, and opportunistic infections, such as pulmonary inflammation caused by Pneumocystis carinii. In this document, however, there is no mention of treatment of alcoholism. In fact, neither the endogenic polyamines themselves, nor any salt, solvate or amide thereof, have ever been proposed for the treatment of alcoholism.